Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus virus that can infect both B lymphocytes and epithelial cells. Depending upon the cell type and its state of differentiation, infection by EBV leads to either lytic replication with cell death or a latent infection. Latent EBV infections are associated with several B-cell and epithelial-cell malignancies including Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas in immunocompromised individuals, nasopharyngeal carcinoma, and some gastric carcinomas. Thus, understanding regulation of EBV latency versus lytic replication is crucial for developing therapies to treat these diseases. The BZLF1 and BRLF1 genes of EBV encode multifunctional proteins essential for lytic replication. While the BZLF1 and BRLF1 promoters are inactive in latently infected cells, cell differentiation and activators of certain cell signaling pathways can induce BZLF1 and BRLF1 expression, promoting EBV reactivation into lytic replication. In this Project, we will (i) identify cellular factors that play key roles in regulating expression of these two immediate-early genes in both B cells and epithelial cells, and (ii) examine how these factors contribute to controlling the balance between latent and lytic EBV infection in a variety of cell types and during cellular differentiation. In conjunction with Project 5, these results may lead to new therapies for treating EBV-associated cancers.